Cytochrome P-450—Catalyzed Formation of Δ ⁴ -VPA, a Toxic Metabolite of Valproic Acid

Abstract

Liver damage induced by the antiepileptic drug valproic acid (VPA) is believed to be mediated by an unsaturated metabolite of the drug, delta 4-VPA. In studies of the biological origin of this hepatotoxic compound, it was found that liver microsomes from phenobarbital-treated rats catalyzed the desaturation of VPA to delta 4-VPA. Indirect evidence suggested that cytochrome P-450 was the responsible enzyme, a conclusion that was verified by studies with a purified and reconstituted form of the hemoprotein, which catalyzed the oxidation of VPA to 4- and 5-hydroxyvalproic acid and to delta 4-VPA. Desaturation of a nonactivated alkyl substituent represents a novel metabolic function of cytochrome P-450 and probably proceeds via the conversion of substrate to a transient free radical intermediate, which partitions between recombination (alcohol formation) and elimination (olefin production) pathways. These findings have broad implications with respect to the metabolic generation of olefins and may explain the increased hepatotoxic potential of VPA when it is administered in combination with potent enzyme-inducing anticonvulsants such as phenobarbital.

Evidence for an Ionic Intermediate in the Transformation of Fatty Acid Hydroperoxide by a Catalase-related Allene Oxide Synthase from the Cyanobacterium Acaryochloris marina

“…We had argued before that the appearance of epoxyalcohols in association with allene oxide synthesis by a purified CYP74 enzyme is evidence of a close parallel in the mechanism of their production (60). (A parallel can be made with conventional P450s, which typically hydroxylate their substrate yet a few can also catalyze desaturation (62)(63)(64)(65)(66)(67).) The fatty acid epoxyalcohols were produced previously when flaxseed AOS (CYP74A1) was presented with unnatural hydroxy-hydroperoxy fatty acid substrates (60).…”

Unusual Cytochrome P450 Enzymes and Reactions

“…However, olefins can also be formed directly by an oxidative mechanism resembling those of recognized desaturases (9,16).…”

Topiramate Enhances the Risk of Valproate‐associated Side Effects in Three Children

“…An increase of the transaminases to 400 U/L, however, is a clear sign of impending liver failure and requires immediate discontinuation of VPA. Underlying metabolic defects, carnitine deficiency, depletion of free acyl-CoA, an increased lipid peroxidation, and abnormal metabolites have been discussed as possible causes of liver failure associated with VPA therapy (4,13).…”